Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression
Open Access
- 10 February 2021
- Vol. 13 (4), 726
- https://doi.org/10.3390/cancers13040726
Abstract
Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression. Methods: Using the RET transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RET transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas. Results: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells. Conclusions: We provide evidence for the tumor−promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.Keywords
Funding Information
- Deutsche Forschungsgemeinschaft (259332240/RTG 2099)
- German Cancer Research Center (CA181)
This publication has 58 references indexed in Scilit:
- T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant MelanomaCancers, 2012
- Monocytic CCR2+ Myeloid-Derived Suppressor Cells Promote Immune Escape by Limiting Activated CD8 T-cell Infiltration into the Tumor MicroenvironmentCancer Research, 2012
- Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma modelProceedings of the National Academy of Sciences, 2011
- Mesenchymal Transition and Dissemination of Cancer Cells Is Driven by Myeloid-Derived Suppressor Cells Infiltrating the Primary TumorPLoS Biology, 2011
- Gr-1+CD11b+ Myeloid Cells Tip the Balance of Immune Protection to Tumor Promotion in the Premetastatic LungCancer Research, 2010
- Tumor-Induced Tolerance and Immune Suppression Depend on the C/EBPβ Transcription FactorImmunity, 2010
- Immune Stimulatory Receptor CD40 Is Required for T-Cell Suppression and T Regulatory Cell Activation Mediated by Myeloid-Derived Suppressor Cells in CancerCancer Research, 2010
- Activation of p38 Mitogen-Activated Protein Kinase Drives Dendritic Cells to Become Tolerogenic inRetTransgenic Mice Spontaneously Developing MelanomaClinical Cancer Research, 2009
- Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancerNature Medicine, 2007
- Transgenic mouse model for skin malignant melanomaOncogene, 1998